Abstract
The C–C Motif Chemokine Ligand 18 (CCL18) is a beta-chemokine sub-family member with immunomodulatory functions in primates. CCL18-dependent migration and epithelial-to-mesenchymal transition of oral squamous cell carcinoma, squamous cell carcinoma of head and neck, breast cancer, hepatocellular carcinoma, non-small cell lung carcinoma, ovarian cancer, pancreatic ductal carcinoma and bladder cancer cells are well-established. In the tumor niche, tumor-associated macrophages produce CCL18 and its overexpression is correlated with reduced patient survival in multiple cancers. Although multiple receptors including C–C chemokine receptor type 3 (CCR3), type 6 (CCR6), type 8 (CCR8) and G-protein coupled estrogen receptor (GPER1) are reported for CCL18, the Phosphatidylinositol Transfer Protein, Membrane-Associated 3 (PITPNM3) receptor is currently considered as its predominant receptor. Characterization of the molecular events and check points associated with the immunosuppressive and cancer progression support functions induced by CCL18 for their potential towards therapeutic applications is an area of active research. Hence, in this study, we assembled 917 signaling events reported to be induced by CCL18 through their studied receptors in diverse cell types as an integrated knowledgebase for reference, data integration and gene-set enrichment analysis of global transcriptomic and/or proteomics datasets.
Data availability
The manually-assembled signaling pathway data is provided in the ‘.xlsx’ format (Supplementary table 1). The pathway data in the ‘.gpml’ format (visualizable through PathVisio tool) with the annotated literature reference to each of the reactions is provided in the Supplementary file 1. This can be exported into multiple formats such as ‘.pdf’, ‘.png’, ‘.jpeg’ formats using the PathVisio tool for enhanced annotation and representation in the future. For the early and efficient incorporation into multiple pathway analysis tools for the enrichment analysis, the pathway data in BioPAX, PSI-MI and also the ‘.gpml’ formats are also made available through WikiPathways (https://www.wikipathways.org/index.php/Pathway:WP5097).
References
Adema GJ, Hartgers F, Verstraten R, de Vries E, Marland G, Menon S, Foster J, Xu Y, Nooyen P, McClanahan T, Bacon KB, Figdor CG (1997) A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells. Nature. https://doi.org/10.1038/42716
Azzaoui I, Yahia SA, Chang Y, Vorng H, Morales O, Fan Y, Delhem N, Ple C, Tonnel AB, Wallaert B, Tsicopoulos A (2011) CCL18 differentiates dendritic cells in tolerogenic cells able to prime regulatory T cells in healthy subjects. Blood. https://doi.org/10.1182/blood-2011-02-338780
Bo S, Donghao S, Guangqi K, Ye T(2018)CC Chemokine Ligand 18 Promotes Cell Proliferation and Metastasis of Urothelial Carcinoma via Activating PI3K/mTOR Signaling in Patient with Renal Transplantation. Urol Int. https://doi.org/10.1159/000492180
Cardoso AP, Pinto ML, Castro F, Costa Â, M., Marques-Magalhães, Â., Canha-Borges, A., Cruz, T., Velho, S. and Oliveira, M.J. (2021) The immunosuppressive and pro-tumor functions of CCL18 at the tumor microenvironment. Cytokine Growth Factor Rev. https://doi.org/10.1016/j.cytogfr.2021.03.005
Catusse J, Wollner S, Leick M, Schröttner P, Schraufstätter I, Burger M (2010) Attenuation of CXCR4 responses by CCL18 in acute lymphocytic leukemia B cells. J Cell Physiol 225(3):792–800
Chang Y, de Nadai P, Azzaoui I, Morales O, Delhem N, Vorng H, Tomavo S, Ait Yahia S, Zhang G, Wallaert B, Chenivesse C, Tsicopoulos A (2010) The chemokine CCL18 generates adaptive regulatory T cells from memory CD4+ T cells of healthy but not allergic subjects. Faseb J. https://doi.org/10.1096/fj.10-162560
Chen G, Cai ZD, Lin ZY, Wang C, Liang YX, Han ZD, He HC, Mo RJ, Lu JM, Pan B, Wu CL, Wang F, Zhong WD (2020) ARNT-dependent CCR8 reprogrammed LDH isoform expression correlates with poor clinical outcomes of prostate cancer. Mol Carcinog. https://doi.org/10.1002/mc.23201
Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, Liu B, Deng H, Wang F, Lin L, Yao H, Su F, Anderson KS, Liu Q, Ewen ME, Yao X, Song E (2011) CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. https://doi.org/10.1016/j.ccr.2011.02.006
Chenivesse C, Chang Y, Azzaoui I, Ait Yahia S, Morales O, Plé C, Foussat A, Tonnel AB, Delhem N, Yssel H, Vorng H, Wallaert B, Tsicopoulos A (2012) Pulmonary CCL18 recruits human regulatory T cells. J Immunol. https://doi.org/10.4049/jimmunol.1003616
Clouse J, Gagnon JP (1999) Panel 5: application of healthcare intervention economic evaluations in healthcare decision-making. Value Health. https://doi.org/10.1046/j.1524-4733.1999.02206.x
Dey G, Radhakrishnan A, Syed N, Thomas JK, Nadig A, Srikumar K, Mathur PP, Pandey A, Lin SK, Raju R, Prasad TS (2013) Signaling network of Oncostatin M pathway. J Cell Commun Signal. https://doi.org/10.1007/s12079-012-0186-y
Guan P, Burghes AH, Cunningham A, Lira P, Brissette WH, Neote K, McColl SR (1999) Genomic organization and biological characterization of the novel human CC chemokine DC-CK-1/PARC/MIP-4/SCYA18. Genomics 56(3):296–302
Hieshima K, Imai T, Baba M, Shoudai K, Ishizuka K, Nakagawa T, Tsuruta J, Takeya M, Sakaki Y, Takatsuki K, Miura R, Opdenakker G, Van Damme J, Yoshie O, Nomiyama H (1997) A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1 alpha/LD78 alpha and chemotactic for T lymphocytes, but not for monocytes. J Immunol 159(3):1140–1149
Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E (2015) PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucl Acids Res. https://doi.org/10.1093/nar/gku1267
Islam SA, Ling MF, Leung J, Shreffler WG, Luster AD (2013) Identification of human CCR8 as a CCL18 receptor. J Exp Med. https://doi.org/10.1084/jem.20130240
Jiang X, Huang Z, Sun X, Zheng X, Liu J, Shen J, Jia B, Luo H, Mai Z, Chen G, Zhao J (2020) CCL18-NIR1 promotes oral cancer cell growth and metastasis by activating the JAK2/STAT3 signaling pathway. BMC Cancer 20(1):632
Jiang X, Wang J, Chen X, Hong Y, Wu T, Chen X, ** pathway resources. Bioinformatics. https://doi.org/10.1093/bioinformatics/btp453
Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GS, Venugopal AK, Telikicherla D, Navarro JD, Mathivanan S, Pecquet C, Gollapudi SK, Tattikota SG, Mohan S, Padhukasahasram H, Subbannayya Y, Goel R, Jacob HK, Zhong J, Sekhar R, Nanjappa V, Balakrishnan L, Subbaiah R, Ramachandra YL, Rahiman BA, Prasad TS, Lin JX, Houtman JC, Desiderio S, Renauld JC, Constantinescu SN, Ohara O, Hirano T, Kubo M, Singh S, Khatri P, Draghici S, Bader GD, Sander C, Leonard WJ, Pandey A (2010) NetPath: a public resource of curated signal transduction pathways. Genome Biol. https://doi.org/10.1186/gb-2010-11-1-r3
Korbecki J, Olbromski M, Dzięgiel P (2020) CCL18 in the progression of Cancer. Int J Mol Sci. https://doi.org/10.3390/ijms21217955
Krohn SC, Bonvin P, Proudfoot AE (2013) CCL18 exhibits a regulatory role through inhibition of receptor and glycosaminoglycan binding. PLoS ONE 8(8):e72321
Kutmon M, van Iersel MP, Bohler A, Kelder T, Nunes N, Pico AR, Evelo CT (2015) PathVisio 3: an extendable pathway analysis toolbox. PLoS Comput Biol 11(2):e1004085
Lane D, Matte I, Laplante C, Garde-Granger P, Carignan A, Bessette P, Rancourt C, Piché A (2016) CCL18 from ascites promotes ovarian cancer cell migration through proline-rich tyrosine kinase 2 signaling. Mol Cancer. https://doi.org/10.1186/s12943-016-0542-2
Leung SY, Yuen ST, Chu KM, Mathy JA, Li R, Chan AS, Law S, Wong J, Chen X, So S (2004) Expression profiling identifies chemokine (C-C motif) ligand 18 as an independent prognostic indicator in gastric cancer. Gastroenterology 127(2):457–469
Lev S, Hernandez J, Martinez R, Chen A, Plowman G, Schlessinger J (1999) Identification of a novel family of targets of PYK2 related to Drosophila retinal degeneration B (rdgB) protein. Mol Cell Biol. https://doi.org/10.1128/mcb.19.3.2278
Li H, Zhang D, Yu J, Liu H, Chen Z, Zhong H, Wan Y (2018) CCL18-dependent translocation of AMAP1 is critical for epithelial to mesenchymal transition in breast cancer. J Cell Physiol. https://doi.org/10.1002/jcp.26164
Li T, Sun X, Xu K (2018) The suppressing role of miR-622 in renal cell carcinoma progression by down-regulation of CCL18/MAPK signal pathway. Cell Biosci. https://doi.org/10.1186/s13578-018-0212-8
Lin X, Chen L, Yao Y, Zhao R, Cui X, Chen J, Hou K, Zhang M, Su F, Chen J, Song E (2015) CCL18-mediated down-regulation of miR98 and miR27b promotes breast cancer metastasis. Oncotarget. https://doi.org/10.18632/oncotarget.4107
Lin L, Chen YS, Yao YD, Chen JQ, Chen JN, Huang SY, Zeng YJ, Yao HR, Zeng SH, Fu YS, Song EW (2015) CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. Oncotarget. https://doi.org/10.18632/oncotarget.5325
Li HY, Cui XY, Wu W, Yu FY, Yao HR, Liu Q, Song EW, Chen JQ (2014) Pyk2 and Src mediate signaling to CCL18-induced breast cancer metastasis. J Cell Biochem 115(3):596–603
Li T, Sun X, Xu K (2018) The suppressing role of miR-622 in renal cell carcinoma progression by down-regulation of CCL18/MAPK signal pathway. Cell Biosci. https://doi.org/10.1186/s13578-018-0212-8
Lin Z, Li W, Zhang H, Wu W, Peng Y, Zeng Y, Wan Y, Wang J, Ouyang N (2016) CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-κB signaling pathway in hepatocellular carcinoma. Tumour Biol. https://doi.org/10.1007/s13277-015-4172-x
Lindhout E, Vissers JL, Hartgers FC, Huijbens RJ, Scharenborg NM, Figdor CG, Adema GJ (2001) The dendritic cell-specific CC-chemokine DC-CK1 is expressed by germinal center dendritic cells and attracts CD38-negative mantle zone B lymphocytes. J Immunol. https://doi.org/10.4049/jimmunol.166.5.3284
Liu X, Xu X, Deng W, Huang M, Wu Y, Zhou Z, Zhu K, Wang Y, Cheng X, Zhou X, Chen L, Li Y, Wang G, Fu B (2019) CCL18 enhances migration, invasion and EMT by binding CCR8 in bladder cancer cells. Mol Med Rep 19(3):1678–1686
Luzina IG, Highsmith K, Pochetuhen K, Nacu N, Rao JN, Atamas SP (2006) PKCalpha mediates CCL18-stimulated collagen production in pulmonary fibroblasts. Am J Respir Cell Mol Biol 35(3):298–305
Nie Y, Chen J, Huang D, Yao Y, Chen J, Ding L, Zeng J, Su S, Chao X, Su F, Yao H, Hu H, Song E (2017) Tumor-Associated Macrophages Promote Malignant Progression of Breast Phyllodes Tumors by Inducing Myofibroblast Differentiation. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-16-2709
Pham TH, Bak Y, Kwon T, Kwon SB, Oh JW, Park JH, Choi YK, Hong JT, Yoon DY (2019) Interleukin-32θ inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancer. Cell Commun Signal. https://doi.org/10.1186/s12964-019-0374-y
Qin Y, Wang J, Zhu G, Li G, Tan H, Chen C, Pi L, She L, Chen X, Wei M, Li Z, Liu Z, Huang D, Liu Y, Zhang X (2019) CCL18 promotes the metastasis of squamous cell carcinoma of the head and neck through MTDH-NF-κB signalling pathway. J Cell Mol Med. https://doi.org/10.1111/jcmm.14168
Raju R, Balakrishnan L, Nanjappa V, Bhattacharjee M, Getnet D, Muthusamy B, Kurian Thomas J, Sharma J, Rahiman BA, Harsha HC, Shankar S, Prasad TS, Mohan SS, Bader GD, Wani MR, Pandey A. A comprehensive manually curated reaction map of RANKL/RANK-signaling pathway. Database (Oxford). 2011 Jul 8;2011:bar021. https://doi.org/10.1093/database/bar021
Raju R, Gadakh S, Gopal P, George B, Advani J, Soman S, Prasad TS, Girijadevi R. Differential ligand-signaling network of CCL19/CCL21-CCR7 system. Database (Oxford). 2015 Oct 26;2015:bav106. https://doi.org/10.1093/database/bav106
Raju R, Nanjappa V, Balakrishnan L, Radhakrishnan A, Thomas JK, Sharma J, Tian M, Palapetta SM, Subbannayya T, Sekhar NR, Muthusamy B, Goel R, Subbannayya Y, Telikicherla D, Bhattacharjee M, Pinto SM, Syed N, Srikanth MS, Sathe GJ, Ahmad S, Chavan SN, Kumar GS, Marimuthu A, Prasad TS, Harsha HC, Rahiman BA, Ohara O, Bader GD, Sujatha Mohan S, Schiemann WP, Pandey A. NetSlim: high-confidence curated signaling maps. Database (Oxford). 2011 Sep 29;2011:bar032.https://doi.org/10.1093/database/bar032
Schutyser E, Richmond A, Van Damme J (2005) Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes. J Leukoc Biol 78(1):14–26
She L, Qin Y, Wang J, Liu C, Zhu G, Li G, Wei M, Chen C, Liu G, Zhang D, Chen X, Wang Y, Qiu Y, Tian Y, Zhang X, Liu Y, Huang D (2018) Tumor-associated macrophages derived CCL18 promotes metastasis in squamous cell carcinoma of the head and neck. Cancer Cell Int 18:120
Shi L, Zhang B, Sun X, Zhang X, Lv S, Li H, Wang X, Zhao C, Zhang H, **e X, Wang Y, Zhang P (2016) CC chemokine ligand 18(CCL18) promotes migration and invasion of lung cancer cells by binding to Nir1 through Nir1-ELMO1/DOC180 signaling pathway. Mol Carcinog 55(12):2051–2062
Song X, Liu W, Yuan X, Jiang J, Wang W, Mullen M, Zhao X, Zhang Y, Liu F, Du S, Rehman A, Tian R, Li J, Frost A, Song Z, Green HN, Henry C, Liu X, Ding X, Wang D, Yao X (2018) Acetylation of ACAP4 regulates CCL18-elicited breast cancer cell migration and invasion. J Mol Cell Biol. https://doi.org/10.1093/jmcb/mjy058
Song X, Wang W, Wang H, Yuan X, Yang F, Zhao L, Mullen M, Du S, Zohbi N, Muthusamy S, Cao Y, Jiang J, **a P, He P, Ding M, Emmett N, Ma M, Wu Q, Green HN, Ding X, Wang D, Wang F, Liu X (2020) Acetylation of ezrin regulates membrane-cytoskeleton interaction underlying CCL18-elicited cell migration. J Mol Cell Biol. https://doi.org/10.1093/jmcb/mjz099
Su et al., 2019: Su Y, Zhou Y, Sun YJ, Wang YL, Yin JY, Huang YJ, Zhang JJ, He AN, Han K, Zhang HZ, Yao Y, Lv XB, Hu HY (2019) Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration by upregulating the expression of UCA1. J Mol Med (Berl). https://doi.org/10.1007/s00109-018-1711-0
Sun Z, Du C, Xu P (2019) ’Surgical trauma-induced CCL18 promotes recruitment of regulatory T cells and colon cancer progression. J Cell Physiol 234(4):4608–4616
Sunitha P, Raju R, Sajil CK, Abhinand CS, Nair AS, Oommen OV, Sugunan VS, Sudhakaran PR (2019) Temporal VEGFA responsive genes in HUVECs: Gene signatures and potential ligands/receptors fine-tuning angiogenesis. J Cell Commun Signal 13(4):561–571
Wang H, Liang X, Li M, Tao X, Tai S, Fan Z, Wang Z, Cheng B, **a J (2017) Chemokine (CC motif) ligand 18 upregulates Slug expression to promote stem-cell like features by activating the mammalian target of rapamycin pathway in oral squamous cell carcinoma. Cancer Sci. https://doi.org/10.1111/cas.13289
Wang Q, Tang Y, Yu H, Yin Q, Li M, Shi L, Zhang W, Li D, Li L (2016) CCL18 from tumor-cells promotes epithelial ovarian cancer metastasis via mTOR signaling pathway. Mol Carcinog 55(11):1688–1699
Ye H, Zhou Q, Zheng S, Li G, Lin Q, Wei L, Fu Z, Zhang B, Liu Y, Li Z, Chen R (2018) Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma. Cell Death Dis 9(5):453
Yuan R, Chen Y, He X, Wu X, Ke J, Zou Y, Cai Z, Zeng Y, Wang L, Wang J, Fan X, Wu X, Lan P (2013) CCL18 as an independent favorable prognostic biomarker in patients with colorectal cancer. J Surg Res. https://doi.org/10.1016/j.jss.2013.01.017
Zhang B, Yin C, Li H, Shi L, Liu N, Sun Y, Lu S, Liu Y, Sun L, Li X, Chen W, Qi Y (2013) Nir1 promotes invasion of breast cancer cells by binding to chemokine (C-C motif) ligand 18 through the PI3K/Akt/GSK3β/Snail signalling pathway. Eur J Cancer 49(18):3900–3913
Zhou Z, Peng Y, Wu X, Meng S, Yu W, Zhao J, Zhang H, Wang J, Li W (2020) CCL18 secreted from M2 macrophages promotes migration and invasion via the PI3K/Akt pathway in gallbladder cancer. Cell Oncol (dordr) 42(1):81–92
Zissel G, Höhne K, Kilic A, Maier C, Ploenes T, Prasse A, Trepel M, Eibel H, Müller-Quernheim J (2011) CCR6 is a receptor for CCL18 expressed on human lung fibroblasts from IPF lungs. Eur Respir J 38(Suppl 55):3232
Zhao C, Zheng S, Yan Z, Deng Z, Wang R, Zhang B (2020) CCL18 promotes the invasion and metastasis of breast cancer through Annexin A2. Oncol Rep https://doi.org/10.3892/or.2019.7426
Acknowledgements
The authors thank Karnataka Biotechnology and Information Technology Services (KBITS), Government of Karnataka, India, for the support to Center for Systems Biology and Molecular Medicine at Yenepoya (Deemed to be University) under the Biotechnology Skill Enhancement Programme in Multiomics Technology (BiSEP GO ITD 02 MDA 2017). Rajesh Raju is a recipient of the Young Scientist Award (YSS/2014/000607) from the Science and Engineering Research Board, Department of Science and Technology (DST), Government of India. Anjana Aravind is a recipient of the Junior Research Fellowship from the Council of Scientific & Industrial Research (CSIR), Government of India. Akhina Palollathil is a recipient of Junior Research Fellowship from the University Grants Commission (UGC), Government of India. D. A. B. Rex is a recipient of Senior Research Fellowship from Indian Council of Medical Research, Government of India.
Funding
Not applicable.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
Authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Aravind, A., Palollathil, A., Rex, D.A.B. et al. A multi-cellular molecular signaling and functional network map of C–C motif chemokine ligand 18 (CCL18): a chemokine with immunosuppressive and pro-tumor functions. J. Cell Commun. Signal. 16, 293–300 (2022). https://doi.org/10.1007/s12079-021-00633-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12079-021-00633-3